Stable hydrazalazine pharmaceutical compositions

ABSTRACT

The present invention relates to stable and highly purified stable hydralazine hydrochloride compositions and stable hydralazine-containing pharmaceutical compositions. A sterile aqueous injectable pharmaceutical composition suitable for parenteral administration is described comprising a therapeutically effective dose of hydralazine hydrochloride in a pharmaceutically acceptable carrier or diluent wherein the hydralazine hydrochloride is essentially free of phthalazines, hydrazine and metal ions. In addition, a stable sterile aqueous pharmaceutical composition comprising hydralazine hydrochloride in a pharmaceutically acceptable salt or diluent is described that is colorless and has no visible particulate matter.

BACKGROUND OF THE INVENTION

The present invention relates to stable and highly purified stablehydralazine hydrochloride compositions and stable hydralazine-containingpharmaceutical compositions.

Hydralazine hydrochloride is a peripheral vasodilator that wasdiscovered about 50 years ago. Hydralazine exerts an antihypertensiveeffect directly on vascular smooth muscle, producing relaxation ofmuscle fibers resulting in a decrease in blood pressure. Hydralazine isan artery-specific direct peripheral vasodilator having an onset ofaction between 10-30 minutes (10-20 minutes given intravenously), amaximum hypotensive effect in 10-80 minutes, and duration of actionbetween 3-4 hours. Hydralazine is extensively metabolized in the body toproducts that are excreted predominantly in the urine, and undergoesN-acetylation, oxidation, hydroxylation, hydrazone formation, andconjugation. Hydralazine is one of the few injectable antihypertensivedrugs that maintain blood flow to kidneys during hypertensive crisis,and the only one to increase blood flow to an already compromisedkidney.

Over 60 million people in the United States suffer from essentialhypertension. About 1% of these people suffers from hypertensive crisisand requires hospital-based acute care. Of the hypertensive crisispatients, 76% are “urgencies” and 24% “emergencies” with end-organdamage. Hypertensive crisis, however, is a medical emergency thatrequires immediate therapy for certain patients in hospital emergencyrooms, operating rooms, and intensive care units. Hypertensive crisis isa life-threatening situation, and includes hypertensive emergencies andhypertensive urgencies characterized by acute elevations in bloodpressure that must be brought under control within hours.

A particularly troubling group of patients with hypertensive crisis arewomen with pregnancy-induced hypertension. Pregnancy inducedhypertension complicates 7% to 10% of the estimated 6.2 millionpregnancies in the United States each year and is considered a majorcause of maternal and fetal morbidity and mortality. These complicationsvary from mild to severe pre-eclampsia and eclampsia. Severepre-eclampsia, which occurs in approximately 10% of preeclampticpatients, usually occurs after 20 weeks gestation and is determined byelevated blood pressures of 140/90 mm Hg or greater. It is characterizedby hypertension, proteinuria, generalized edema and disturbances incoagulation and liver function. Pre-eclampsia can progress to eclampsia,a convulsive disorder that can cause cerebral hemorrhage and maternaldeath. Complications resulting from pre-eclampsia and eclampsia are amajor cause of maternal deaths around the world, and account for about17% of maternal deaths in the United States. About half of these deathsin the United States are due to cardiovascular and central nervoussystem complications, including hemorrhage and embolism. Moreover, inwomen without proteinuria, the risk of fetal death rises more thanthree-fold from 6.2/1000 if the diastolic blood pressure is 75-84 mmHgto 19.2/1000 if the diastolic blood pressure is 104 mmHg.

Hydralazine hydrochloride is commercially available in both oral tabletand sterile injectable dosage forms. The sterile injectable form is usedto lower blood pressure primarily in pregnant women suffering fromsevere preeclampsia and eclampsia in hypertensive crisis situations. Theoral tablet form of hydralazine hydrochloride is used in patientsrequiring long-term management of their hypertension after such a crisishas abated. Hydralazine hydrochloride is very unstable in all of thesterile injectable pharmaceutical formulations currently available.Continuing instability problems with injectable hydralazinehydrochloride, for example, have plagued pharmaceutical manufacturersfor many years, forcing these companies to remove their injectablehydralazine products from the marketplace. In all current embodiments ofits injectable formulations, hydralazine hydrochloride forms smallyellow-green particles following storage from 1 to about 2 months whenhydralazine is stored at 40° C. and after from 6 to about 9 monthsstorage at 25° C. Although the identification of the yellow-greenparticles has yet to be confirmed, it is believed that the particles areinsoluble polymeric products formed by reaction of hydralazine andcontaminating by-products of hydralazine manufacture during storage ofhydralazine solutions.

Despite its unique pharmacologic properties as a hypertensive drug, thetherapeutic use of hydralazine hydrochloride has been limited by itsinstability during storage. A stable hydralazine pharmaceuticalcomposition that is more easily manufactured and does not degrade orproduce particulate matter during extended storage of the bulk drugsubstance or its formulations does not currently exist. Moreover, amethod of manufacture of hydralazine hydrochloride that provides apharmaceutical quality product that is free of contaminating by-productssuch as hydrazine, metal ions, or chlorinated pyridazine-containingcompounds is not currently available.

A conventional method of manufacture that is widely used for thecommercial manufacture of hydralazine hydrochloride is disclosed in U.S.Pat. No. 2,484,029 to M. Hartmann and J. Druey. According to Hartmannand Druey, hydrazine derivatives of pyridazine compounds are formed byreacting a hydrazine with a pyridazine compound of the desired structurebut containing a group in the ortho position to a ring nitrogen that isreplaceable by a hydrazine radical. Examples of such replaceable groupsare a halogen, an esterified hydroxyl group, or an aryloxy or thioethergroup. Compounds containing the pyridazine ring that may be used asstarting materials are substituted or unsubstituted compounds including1-chlorophthalazine, 1-chloromethylphthalazine,1-chloro-4-ethylphthalazine, 1-chloro-4-propylphthalazine,1-chloro-butylphthalazine, 1-chloro-4-benzylphthalazine,1-chloro-7-methoxyphthalazine, 1-chloro-7,8-dimethoxyphthalazine,1-chloro-6-hydroxyphthalazine, 1-chloro-4-phenylphthalazine,1-chloro-4-(p-methoxyphenyl)phthalazine, 1,4-dichlorophthalazine,3-chloropyridazine, 3-chloro-6-methylpyridazine,3-chloro-6-phenylpyridazine, 3-chloro-6-(p-hydroxyphenyl)pyridazine,6-chloro-3-phenylpyrido-2′,3′,4,5-pyridazine, and6-chloro-3-phenylpyrido-3′,4′,4,5-pyridazine. Insofar as the startingmaterials such as the phthalazines or pyridazines are not known, theycan be obtained from corresponding oxocarboxylic acids by reaction withhydrazine. The oxo compounds, for example, the phthalazones orpyridazones thus obtained, may be converted into their chlorinecompounds, for example, by treatment with phosphorus oxychloride. Ashydrazines, hydrazine itself or its substitution products wherein anitrogen atom may form part of a ring, as, for example, morpholine orpiperidine, may be employed. Examples of suitable hydrazines are:hydrazine, methylhydrazine, benzylhydrazine, asymmetricaldimethylhydrazine, symmetrical dimethylhydrazine, propylhydrazine,allylhydrazine, N-methyl-N-butylhydrazine, N-aminopiperidine,N-aminomorpholine, 3-methyl-cyclohexylhydrazine, and the like. Also,these hydrazines may be employed in the form of their salts. Theconversion with hydrazines is carried out suitably in the presence ofdiluents, if desired also in the presence of condensing agents, and ifdesired in the presence of catalysts such as copper powder.

According to the method of manufacture of U.S. Pat. No.2,484,029,1-chlorophthalazone is prepared by treating 30 parts by weightof 1-phthalazinone with phosphorus oxychloride as described in Berichtedes Deutsche Chemische Gesellschaft, vol. 26, page 521, 1893. Thefreshly obtained yet moist chloro compound is heated on a water bath fortwo hours in a mixture of 100 parts by volume of ethyl alcohol and 90parts by volume of hydrazine hydrate. The hot solution is filtered, andhydralazine crystallizes out in yellow needles on cooling. It isfiltered with suction and washed with cold ethyl alcohol. The compoundis crystallized from methyl alcohol. On warming in alcoholic or aqueoushydrochloric acid, hydralazine hydrochloride is obtained.

When manufactured according to the methods of manufacture of U.S. Pat.No. 2,484,029, the product, hydralazine hydrochloride bulk solid, isknown to contain residuals from the manufacturing process including, forexample, hydrazine, chlorinated or chlorophosphorylated phthalazine orpyridazine intermediates, and phthalazone or pyridazone precursors tothe chlorophthalazine or chloropyridazine raw material. In addition, ifcopper powder was employed as a catalyst, the product, hydralazinehydrochloride bulk solid, also contains low concentrations of copper ion(Cu⁺²).

Because hydrazine is a very toxic chemical, human exposure to hydrazineis severely restricted. Thus, the U.S. Pharmacopeia Official Monographfor hydralazine hydrochloride, for example, requires that pharmaceuticalquality hydralazine hydrochloride contain no more than 0.1% hydrazine byweight.

Hydralazine is known to chelate metal ions. Sinha and Motten[Biochemical and Biophysical Research Communications 105(3): 1044-1051(1982)] report that hydralazine oxidizes rapidly in the presence ofoxygen and metal ions such as Cu⁺², Fe⁺², and Fe⁺³ through free radicalintermediates in a manner similar to other hydrazine derivatives.

When manufactured according to conventional methods of manufacture,hydralazine hydrochloride undergoes degradation during storage tointensely colored, insoluble polymeric products. The numerousdegradation products that form during storage have not been completelyidentified and characterized chemically, but it is believed that theyare the products of reactions such as chelation with metal ions,oxidation, reaction of residual hydrazine raw material with chlorinatedintermediates that were incompletely removed during manufacturing, andreaction of hydralazine with chlorinated intermediates that wereincompletely removed during manufacturing.

It is an object of the present invention to manufacture hydralazinehydrochloride of high pharmaceutical quality that is free ofcontaminating by-products.

It is an object of the present invention to manufacture hydralazinehydrochloride of high pharmaceutical quality that is free ofcontaminating by-products such as hydrazine, metal ions, or chlorinatedpyridazine-containing compounds.

It is a further object of the present invention to manufacture a stablepharmaceutical formulation of hydralazine hydrochloride that is free ofcontaminating by-products such as hydrazine, metal ions, or chlorinatedpyridazine-containing compounds.

It is a further object of the present invention to manufacture a stablehydralazine hydrochloride pharmaceutical composition that does notdegrade or produce particulate matter during extended storage of thebulk drug substance or its liquid formulations.

It is a further object of the present invention to manufacture a stableinjectable pharmaceutical formulation containing hydralazinehydrochloride that has no visible particulate matter for a time morethan 30 months after manufacture.

It is a further object of the present invention to manufacture a stableinjectable pharmaceutical formulation containing hydralazinehydrochloride that has less than 6000 10 micron particles per containeror 600 25 micron particles per container for a time more than 30 monthsafter manufacture.

It is a further object of the present invention to produce hydralazinehydrochloride that is stable in sterile injectable pharmaceuticalformulations.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the subvisible particle count for the 25 micronparticles for each of the hydralazine hydrochloride solutions forprepared in Examples 4-7 stored at 40° C. for up to 118 days.

FIG. 2 is a graph of the subvisible particle count for the 10 micronparticles for each of the hydralazine hydrochloride solutions forprepared in Examples 4-7 stored at 40° C. for up to 118 days.

FIG. 3 is a ¹H nuclear magnetic resonance (NMR) spectrum of1-chlorophthalazine that was prepared conventionally.

FIG. 4 is a ¹H nuclear magnetic resonance (NMR) spectrum of1-chlorophthalazine that was prepared in accordance with the presentinvention.

FIG. 5 is an HPLC chromatogram of hydralazine hydrochloride that wasprepared conventionally. An arrow indicates the presence of eachimpurity peak.

FIG. 6 is an HPLC chromatogram of hydralazine hydrochloride that wasprepared in accordance with the present invention. An arrow indicatesthe presence of each impurity peak.

BRIEF SUMMARY OF THE INVENTION

In accordance with the present invention, disclosed is a method ofpreparing hydralazine hydrochloride, comprising the steps of:

-   -   a. heating a first mixture of 1-phthalazinone with phosphorous        oxychloride thereby providing 1-chlorophthalazine;    -   b. contacting said 1-chlorophthalazine with an alkane having        from about 5 to about 7 carbon atoms;    -   c. removing said alkane from said 1-chlorophthalazine;    -   d. contacting said 1-chlorophthalazine obtained in step c with        tetrahydrofuran;    -   e. removing said tetrahydrofuran from said 1-chlorophthalazine;    -   f. heating a second mixture containing 1-chlorophthalazine from        step e and hydrazine hydrate thereby providing hydralazine;    -   g. separating said hydralazine from said second mixture; and    -   h. contacting said hydralazine from step g with hydrochloric        acid thereby providing hydralazine hydrochloride.

In accordance with a specific embodiment of the present invention,disclosed is a method of preparing a chlorinated heterocyclic compoundhaving the formula:

comprising the steps of:

-   -   a. heating a first mixture of a compound having the formula:

with phosphorous oxychloride thereby providing an admixture containingsaid chlorinated heterocyclic compound;

-   -   b. contacting said admixture with an alkane having from about 5        to about 7 carbon atoms;    -   c. removing said alkane from said compound 1.

DETAILED DESCRIPTION OF THE INVENTION

The method of preparing hydrazine derivatives according to the presentinvention comprises essentially two steps. In the first step, stablechlorinated heterocyclic compounds are prepared by the reaction ofphosphorous oxychloride with compounds having the formula:

In the second step, highly purified hydrazine derivatives are preparedby the reaction of hydrazines with the stable chlorinated heterocycliccompounds having the formula:

Unlike the methods of the prior art, the method of the present inventionprovides highly purified hydrazine derivatives in large part because ofthese stable chlorinated heterocyclic intermediates.

In particular, disclosed is a method of preparing hydralazinehydrochloride, comprising essentially two steps. In the first step,stable 1-chlorophthalazine is prepared by the reaction of phosphorousoxychloride with 1-phthalazinone having the formula:

contacting the 1-chlorophthalazine with an alkane having from about 5 toabout 7 carbon atoms, and removing the alkane from 1-chlorophthalazine.

In the second step, highly purified hydralazine is prepared by thereaction of hydrazine with the stable 1-chlorophthalazine having theformula:

In accordance with the present invention, the stable chlorinatedheterocyclic intermediates are prepared by contacting an admixture ofthe chlorinated heterocyclic compounds produced in the first step withan alkane having from about 5 to about 7 carbon atoms and removing thealkane. Partitioning the chlorinated heterocyclic intermediates betweenthe admixture and the alkane provides the production of stable,free-flowing powder chlorinated heterocyclic compounds.

In a preferred embodiment of the present invention, highly purifiedhydralazine hydrochloride is prepared from 1-phthalazinone by heating afirst mixture of 1-phthalazinone with phosphorous oxychloride therebyproviding 1-chlorophthalazine, contacting said 1-chlorophthalazine withan alkane having from about 5 to about 7 carbon atoms, removing saidalkane from said 1-chlorophthalazine and contacting the1-chlorophthalazine with tetrahydrofuran. Advantageously, thisembodiment of the present invention uses POCl₃, and removes excess POCl₃and other undesired by-products without use of bases. After removing thetetrahydrofuran, the 1-chlorophthalazine is heated in a second mixturewith hydrazine hydrate. The hydralazine compound produced is separatedfrom this second mixture and converted to hydralazine hydrochloride withhydrochloric acid.

In a more preferred embodiment of the present invention, the alkanehaving from about 5 to about 7 carbon atoms is hexane.

In a more preferred embodiment the method of the present invention isperformed in vessels having a non-metallic contact surface.

In a more preferred embodiment of the present invention, the firstmixture is heated to a temperature from about 70° to about 85° C. for atime sufficient to convert 1-phthalazinone to 1-chlorophthalazine.

In a more preferred embodiment of the present invention, the secondmixture is prepared by adding 1-chlorophthalazine to said hydrazineprior to heating. In a most preferred embodiment of the presentinvention, the said second mixture is heated to a temperature from about60 to about 70° C. for a time sufficient to convert 1-chlorophthalazineto hydralazine.

In the most preferred embodiment of the present invention, the alkane ishexane, the first mixture is heated to a temperature from about 70° toabout 85° C. for a time sufficient to convert 1-phthalazinone to1-chlorophthalazine, and the second mixture is prepared by adding1-chlorophthalazine to said hydrazine prior to heating at a temperaturefrom about 60° to about 70° C. for a time sufficient to convert1-chlorophthalazine to hydralazine.

Hydralazine hydrochloride compositions prepared in accordance with thesynthetic method of the present invention are surprisingly highly pureand essentially free of phthalazines, hydrazine and metal ions that arenormally found in stainless steel resulting in a stable activepharmaceutical ingredient. In accordance with the present invention, theterms “essentially free of phthalazine compounds” or “essentially freeof phthalazines” refers to compositions comprising less than about 1% byweight of phthalazine compounds. In a more preferred embodiment of thepresent invention, hydralazine hydrochloride compositions comprise lessthan about 0.5% by weight of phthalazine compounds. In accordance withthe present invention, the terms “essentially free of hydrazinecompounds” or “essentially free of hydrazines” refers to compositionscomprising less than about 0.0005% by weight of hydrazine compounds.

In accordance with the present invention, the terms “essentially free ofmetal ions” refers to compositions comprising less than about 15 partsper million of metal ions. In a more preferred embodiment of the presentinvention, hydralazine hydrochloride compositions comprise less thanabout 10 parts per million metal ions. The individual metal ions areselected from the group consisting of copper ions, iron ions, manganeseions, nickel ions, molybdenum ions, and cobalt ions. In accordance withthe present invention, the concentration of the individual metal ionsmight vary; however, the aggregate concentration of metal ions ispreferably less than about 15 parts per million and more preferably lessthan about 10 parts per million.

In accordance with a preferred embodiment of the present invention, thehydralazine hydrochloride compositions comprise less than 1% by weightphthalazine compounds, less than about 0.0005% by weight hydrazine, andless than about 15 parts per million metal ions. In accordance with amore preferred embodiment of the present invention, the hydralazinehydrochloride compositions comprise less than 0.5% by weight phthalazinecompounds, less than about 0.0005% by weight hydrazine, and less thanabout 15 parts per million metal ions. In accordance with a mostpreferred embodiment of the present invention, the hydralazinehydrochloride compositions comprise less than 0.5% by weight phthalazinecompounds, less than about 0.0005% by weight hydrazine, and less thanabout 10 parts per million metal ions.

In accordance with a more preferred embodiment of the present invention,reaction vessels for the preparation of hydralazine hydrochloride areconstructed with solution contact surfaces that are essentiallynon-metallic. In accordance with a most preferred embodiment of thepresent invention, reaction vessels for the preparation of hydralazinehydrochloride are constructed with solution contact surfaces that arenon-metallic.

The differences in the purity of hydralazine hydrochloride that wasprepared in accordance with the present invention relative tohydralazine hydrochloride prepared conventionally are shown bycomparison of the HPLC chromatograms of each material (FIGS. 6 and 5,respectively). Clearly, the number of impurity peaks (shown by arrows)in hydralazine hydrochloride of the present invention is less than thenumber present in hydralazine hydrochloride conventionally prepared.Likewise, the intensity of each impurity peak (e.g., the peak height orarea under the peak) is less in hydralazine hydrochloride of the presentinvention than in hydralazine hydrochloride conventionally prepared.

The synthetic method of the present invention not only provides a stableand highly purified hydralazine hydrochloride composition, itunexpectedly and surprisingly provides a stable hydralazine-containingpharmaceutical composition. In accordance with the present invention, “astable hydralazine pharmaceutical composition” refers to one that iseither manufactured without significant degradation, one that does notdegrade significantly during storage or one that does not productsignificant levels of particulate (visible or submicron) matter duringextended storage. In accordance with the present invention, hydralazinepharmaceutical compositions include finished dosage forms such astablets and liquids for oral administration, and liquids for parenteraladministration.

Pharmaceutical compositions of the present invention suitable forparenteral administration comprise sterile aqueous injection solutionsof hydralazine hydrochloride. The sterile aqueous injection solutions ofthe present invention preferably comprise a therapeutically effectivedose of hydralazine hydrochloride in a pharmaceutically acceptablecarrier or diluent in a sealed container. In accordance with one aspectof the present invention, these sterile aqueous solutions are preferablyisotonic with the blood of the intended recipient.

In accordance with one aspect of the present invention, thepharmaceutical compositions comprise sterile aqueous solutions ofhydralazine hydrochloride that is essentially free of phthalazines. Inaccordance with a preferred embodiment of the present invention, thepharmaceutical composition comprises hydralazine hydrochloride whereinthe hydralazine has less than about 1% by weight of phthalazinecompounds associated with it. In accordance with a more preferredembodiment of the present invention, the composition compriseshydralazine hydrochloride wherein the hydralazine has less than about0.5% by weight of phthalazine compounds associated with it.

In accordance with another aspect of the present invention, thepharmaceutical compositions comprise sterile aqueous solutions ofhydralazine hydrochloride that are essentially free of hydrazine. Inaccordance with a preferred embodiment of the present invention, thepharmaceutical composition comprises hydralazine hydrochloride whereinthe hydralazine has less than about 0.0005% by weight of hydrazineassociated with it.

In accordance with another aspect of the present invention, thepharmaceutical compositions comprise sterile aqueous solutions ofhydralazine hydrochloride that are essentially free of metal ions. Inaccordance with a preferred embodiment of the present invention, thecomposition comprises hydralazine hydrochloride wherein the hydralazinehas less than about 15 parts per million metal ions associated with it.In accordance with a more preferred embodiment of the present invention,the pharmaceutical composition comprises hydralazine hydrochloridewherein the hydralazin has less than about 10 parts per million metalions associated with it.

In accordance with a more preferred embodiment of the present invention,the pharmaceutical compositions comprise sterile aqueous solutions ofhydralazine hydrochloride that are essentially free of phthalazines,hydrazine and metal ions. In accordance with a most preferred embodimentof the present invention, the pharmaceutical compositions comprisesterile aqueous solutions of hydralazine hydrochloride contain less than1% by weight of phthalazine compounds, less than 0.0005% by weighthydrazine and less than 15 parts per million metal ions.

The sterile aqueous injection solutions of the present inventionpreferably comprise a therapeutically effective dose of hydralazinehydrochloride, that is, an amount of hydralazine hydrochloride that iseffective in lowering the blood pressure of a patient when administered.In accordance with one aspect of the present invention, thetherapeutically effective dose is from about 5 to about 20 mg and theconcentration of hydralazine hydrochloride is from about 5 to about 20mg/mL. In accordance with a preferred embodiment of the presentinvention, the therapeutically effective dose is from about 5 to about20 mg and the concentration of hydralazine hydrochloride is 20 mg/mL. Inaccordance with a most preferred embodiment of the present invention,the therapeutically effective dose is from about 5 to about 20 mg andthe concentration of hydralazine hydrochloride 5 mg/mL.

The sterile aqueous injection solutions of the present inventionpreferably comprise a therapeutically effective dose of hydralazinehydrochloride in a pharmaceutically acceptable liquid carrier or diluentfor parenteral administration to a patient. In general, water, saline,aqueous dextrose (glucose), and related sugar solutions and glycols suchas propylene glycol or polyethylene glycols are suitable carriers forparenteral solutions. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, and other standard reference textsin this field. In accordance with the present invention,pharmaceutically acceptable carriers and diluents preferably includesodium chloride (saline), preservatives such as methyl- orpropyl-paraben, or polyethylene glycol in sterile water for injection.

In accordance with the present invention, a preferred pharmaceuticallyacceptable diluent includes poly(ethylene glycol) (PEG) having anaverage molecular weight of 200, 400, 600, 1,000, 3,000, 5,000, or10,000 Daltons in sterile water for injection. In a more preferredembodiment of the present invention, the polyethylene glycol is“essentially free” of ethylene oxide and ethylene glycol, i.e., it meetsU.S. Pharmacopeial monograph standards for absence of ethylene oxide andethylene glycol. In a most preferred embodiment of the presentinvention, the pharmaceutical formulation of hydralazine hydrochloridecontains 5 mg/mL hydralazine hydrochloride, 0.325 mg/mL methyl paraben,0.175 mg/mL propyl paraben, and 100 mg/mL poly(ethylene glycol) havingan average molecular weight of 400 Da in sterile water for injection.Surprisingly, we have observed that the pH of hydralazine formulationswith polyethylene glycol are stable over an extended period of timewithout significant deviations. Significant deviations in pH can bemonitored in a number of ways including observing physical changes (e.g.color) in the solutions. This is a significant and unexpected advantageover hydralazine formulations of the prior art.

Preferably, the hydralazine pharmaceutical formulations of the presentinvention have a pH of from about 4.0 to about 4.5. In accordance with amore preferred embodiment of the present invention, the hydralazinepharmaceutical formulations have a pH of about 4.2.

The sterile aqueous injection solutions of the present inventionpreferably comprise a therapeutically effective dose of hydralazinehydrochloride in a unit dose or multi-dose container. In accordance witha preferred embodiment of the present invention, the therapeuticallyeffective dose of hydralazine hydrochloride is provided in a sealedampoule or vial. In accordance with a most preferred embodiment of thepresent invention, there is provided an injectable, stable, sterilecomposition comprising a compound of sterile aqueous solutions ofhydralazine hydrochloride that are essentially free of phthalazines,hydrazine and metal ions in a sealed container.

ILLUSTRATIVE EXAMPLES OF THE INVENTION Example 1 Conventional Method ofPreparation of Hydralazine Hydrochloride

A. Conventional Preparation of 1-Chlorophthalazine.

One mole equivalent (10 g) of 1(2H)-phthalazinone and 7.7 moleequivalents (82.5 g, 50.1 mL) of phosphorus oxychloride were chargedinto a 100-mL, 3-necked flask fitted with a temperature probe andcondenser. The slurry was stirred and heated to 70° C., and then theheat source was removed. The mixture was allowed to cool to roomtemperature, and then was poured in portions over 500 g of ice. Afterthe initial addition of the reaction mixture, a violent exotherm wasobserved, and a portion of the solution spilled over the sides of thecontainer. Ice quenching was completed with extreme caution but withoutfurther incident.

Alternative workups were also examined. As a first alternative, afterthe reaction mixture reached room temperature, it was concentrated byheating at 45° C. under vacuum. The resulting yellow slurry was added inportions to 3 volumes of cold, deionized water. Once again, control ofexothermic reactions that occurred during this quenching step wasdifficult. As a second alternative, after the reaction mixture reachedroom temperature, it was concentrated by heating at 45° C. under vacuum.To the resulting oily yellow paste was added 5 volumes of toluene, andthe resulting biphasic solution was concentrated by heating at 45° C.under vacuum to remove the phosphorus oxychloride/toluene azeotrope. Theprocess was repeated a second time. The resulting yellow pastesolidified into an unworkable solid that was discarded. As a thirdalternative, after the reaction mixture reached room temperature, it wasconcentrated by heating at 45° C. under vacuum. To the resulting oilyyellow paste was added 2 volumes of toluene, and the resulting biphasicsolution was concentrated by heating at 45° C. under vacuum to removethe phosphorus oxychloride/toluene azeotrope. The process was repeated asecond time, and then 2 volumes of tetrahydrofuran were added. Theresulting slurry was stirred and cooled to 0° C. and then was filteredto isolate a light yellow solid. The filtrate was treated as describedin the following paragraph.

The aqueous mixture was rendered basic by the addition of 5 N sodiumhydroxide solution. A light yellow precipitate formed. The solid wasisolated by extraction into dichloromethane and concentration of theresulting extracts to dryness. A moist cake of 1-chlorophthalazine wasthus obtained in yields that ranged from 80% to 440% of theoretical. Ifthe moist cake was allowed to dry, or if this material was not usedimmediately, it darkened and underwent degradation to a mixture of thedesired product, 1-chlorophthalazine, and multiple by-products. Toprevent this loss and contamination, freshly obtained, moist chlorocompound was used immediately.

B. Conventional Preparation of Hydralazine.

A solution was prepared to contain 1 part by weight 1-chlorophthalazine,100 parts by volume of ethyl alcohol and 90 parts by volume of hydrazinehydrate. It was heated for two hours and then filtered. On cooling,1-hydrazinophthalazine (hydralazine) precipitated from the filtrate asyellow needles, which were isolated by filtration and washed with coldethyl alcohol. The product was precipitated from methyl alcohol. Theproduct melted, when rapidly heated, at 172-173° C. Typical yields were30-60%.

C. Conventional Preparation of Hydralazine Hydrochloride.

On warming in alcoholic or aqueous hydrochloric acid, hydralazinehydrochloride of melting point 273° C. (with decomposition) wasobtained.

Example 2 Novel Method for the Preparation of Hydralazine Hydrochloride

A. Novel Preparation of 1-Chlorophthalazine.

One mole equivalent (250 g) of 1 (2H)-phthalazinone and 3.8 moleequivalents (775 g) of phosphorus oxychloride were charged into a 3-L,3-necked flask fitted with a temperature probe and condenser. The slurrywas stirred and heated to 80° C., maintained at that temperature for 30minutes, and then the heat source was removed. Thin layerchromatographic analysis indicated that conversion to1-chlorophthalazine was complete. The mixture was allowed to cool toroom temperature, and 1.6 L of hexanes was added. The resulting slurrywas stirred for several minutes, and the hexane layer was decanted.Addition of hexanes and decantation was repeated two more times. Then1.6 L of tetrahydrofuran was added; as the solution was stirred, anoff-white precipitate formed. The solid was isolated by filtration andwashed with 250 mL of cold tetrahydrofuran to afford an 85-100% yield of1-chlorophthalazine, the desired product, as an off-white powder thatcould be dried and characterized.

B. Novel Preparation of Hydralazine.

To a 2-L, 3-necked, round-bottom flask fitted with a temperature probeand condenser were charged 700 mL of ethanol and 7.6 mole equivalents(630 mL) of hydrazine hydrate, and the solution was cooled to <10° C.One (1) mole equivalent (280 g) of 1-chlorophthalazine (solid) was addedin portions at a rate to maintain the solution temperature at <20° C.The solution was stirred and heated to 60-70° C. After 1 hour attemperature, the hot solution was filtered to remove any insolubleby-products, and the filtrate was cooled to 0-5° C. A light yellow solidformed in the cold solution, and was isolated by filtration and washedwith cold ethanol. The resulting product, hydralazine free base, wasdried to constant mass and characterized. Typical yields were in therange 77-80%. The hydralazine thus obtained could be used in the nextstep without purification.

C. Novel Preparation of Hydralazine Hydrochloride.

Hydralazine free base (1 part by weight) was heated in 6 to 7 parts byvolume of 15% hydrochloric acid to a temperature of 70-80° C. Thesolution was filtered hot to remove traces of insoluble materials thatwere undesired by-products of the preceding step. Ethanol (6 to 7 partsby volume) was added to the filtrate. As the resulting solution cooledto ambient temperature and then further to 3-8° C., an off-white to paleyellow precipitate of the desired product, hydralazine hydrochloride,was obtained. Typical yields were 80-90%.

D. Recrystallization of Hydralazine Hydrochloride.

A single necked, round-bottom flask was charged with 1 part by weight ofhydralazine hydrochloride (from the preceding step) and 6 parts (byvolume) of 1% hydrochloric acid. The solution was stirred and heated todissolve the solid, and then filtered hot, if necessary, to removetraces of colored insoluble by-products. Ethanol (6 parts by volume) wasadded to the hot (filtered) solution. As the resulting solution cooled,an off-white precipitate of purified hydralazine hydrochloride formed.The recrystallized, purified product was isolated by filtration andwashed with fresh, cold ethanol. The desired product, pharmaceuticalquality hydralazine hydrochloride, containing I ss than 0.5% by weightof undesired by-products, less than 5 ppm of trace metals, and nodetectable residual hydrazine, was obtained in 85-100% yield. Meltingpoint: 273.9-274.3° C. HPLC Chromatogram: FIG. 6. NMR Spectrum (DMSO)3.45 (s), 8.15 (t), 8.25 (t) and 9.7 (s) ppm.

Example 3 Preparation of Conventional Hydralazine HydrochloridePharmaceutical Composition

A pharmaceutical formulation of hydralazine hydrochloride prepared inExample 1 was prepared to contain 20 mg/mL hydralazine hydrochloride,0.65 mg/mL methyl paraben, 0.35 mg/mL propyl paraben, and 100 mg/mLpropylene glycol in sterile water for injection. The formulation waspackaged in a glass bottle that was closed and sealed with anelasteomeric stopper. Within hours of preparation, a flocculent yellowprecipitate was observed in the solution. Within 24 hours, the amount ofyellow particulate in the solution increased dramatically.

Example 4 Preparation of Stable Hydralazine Hydrochloride PharmaceuticalComposition

A liquid pharmaceutical formulation of hydralazine hydrochlorideprepared in Example 2 was prepared to contain 5 mg/mL hydralazinehydrochloride and 0.7% NaCl in sterile water for injection. Theformulation was packaged in a glass bottle that was closed and sealedwith an elasteomeric stopper.

Example 5 Preparation of Stable Hydralazine Hydrochloride PharmaceuticalComposition

A liquid pharmaceutical formulation of hydralazine hydrochlorideprepared in Example 2 was prepared to contain 5 mg/mL hydralazinehydrochloride, 0.1625 mg/mL methyl paraben, 0.0875 mg/mL propyl paraben,and 25 mg/mL propylene glycol in sterile water for injection. Theformulation was packaged in a glass bottle that was closed and sealedwith an elasteomeric stopper.

Example 6 Preparation of Stable Hydralazine Hydrochloride PharmaceuticalComposition

A liquid pharmaceutical formulation of hydralazine hydrochlorideprepared in Example 2 was prepared to contain 5 mg/mL hydralazinehydrochloride, 0.65 mg/mL methyl paraben, 0.35 mg/mL propyl paraben, and100 mg/mL propylene glycol in sterile water for injection. Theformulation was packaged in a glass bottle that was closed and sealedwith an elasteomeric stopper.

Example 7 Preparation of Stable Hydralazine Hydrochloride PharmaceuticalComposition

A liquid pharmaceutical formulation of hydralazine hydrochlorideprepared in Example 2 was prepared to contain 20 mg/mL hydralazinehydrochloride, 0.65 mg/mL methyl paraben, 0.35 mg/mL propyl paraben, and100 mg/mL propylene glycol in sterile water for injection. Theformulation was packaged in a glass bottle that was closed and sealedwith an elasteomeric stopper.

Example 8 Analysis of Stable Hydralazine Hydrochloride

Hydralazine hydrochloride was prepared as in Example 2 and subjected tochemical analysis. The results of this chemical analysis id shown inTable 1 below:

TABLE 1 Analysis of Stable Hydralazine Hydrochloride HydralazineHydrochloride USP prepared as Analytical Test Specifications in Example2 Hydrazine impurity NMT 0.001% 0.000% Chromatographic Purity(impurities) NMT 1.0%  0.2% Phthalazine impurity None  0.0% Hydralazinecontent 98-102% 100.8% Stainless Steel Metal Ions None    10 ppm Organicvolatile impurities: Ethanol NMT 5000 ppm 324-479 ppm Hexanes NMT 290ppm Not Detected Tetrahydrofuran NMT 5000 ppm Not Detected

Example 9 Evaluation of Storage Stability of Hydralazine Hydrochloridein Solutions for Pharmaceutical Administration

The hydralazine hydrochloride solutions prepared in accordance withExamples 4-7 were stored inverted both at +25 and +40° C. Each solutionwas analyzed prior to packaging in the glass bottles and after two weeksand 4 weeks of storage. At each of these time intervals, the solutionswere visually analyzed for color and visible particulate matter, andinstrumentally by light obscuration for subvisible particulate matterhaving particles with a diameter of >10 microns and >25 microns. (seeFIGS. 1 and 2).

After 118 days of storage, the solutions were visually analyzed forcolor and visible particulate matter, instrumentally by lightobscuration for subvisible particulate matter having particles with adiameter of >10 microns and >25 microns, and by HPLC assay forhydralazine content, methylparaben content, and propylparaben content.

TABLE 2 Characteristics of Hydralazine Hydrochloride Solutions After 118Days of Storage at +25° C. Example 4 Example 5 Example 6 Example 7 TestsObservations Visual Appearance Clear & colorless Clear & colorless Clear& colorless Clear, light yellow Assay by HPLC (As % of (As % of (As % of(As % of original value) original value) original value) original value)Hydralazine 101.1% 100.3% 99.2% 100.0% Methyl paraben Not present 100.6%99.8% 100.2% Propyl paraben Not present  98.1% 95.3%  98.4% VisibleParticulate None None None None

TABLE 3 Characteristics of Hydralazine Hydrochloride Solutions After 118Days of Storage at +40° C. Example 4 Example 5 Example 6 Example 7 TestsObservations Visual Appearance Clear & colorless Clear & colorless Clear& colorless Clear, light yellow Assay by HPLC (As % of (As % of (As % of(As % of original value) original value) original value) original value)Hydralazine 101.1% 100.3% 99.2% 100.0% Methyl paraben Not present 100.6%99.8% 100.2% Propyl paraben Not present  98.1% 95.3%  98.4% VisibleParticulate None None None None Subvisual Particulate (Per container)(Per container) (Per container) (Per container) >10 microns 1210 20801770 2370 >25 microns  60  100  160  60

Example 10 Preparation of Stable Hydralazine HydrochloridePharmaceutical Composition

A liquid pharmaceutical formulation for parenteral administration ofhydralazine hydrochloride was prepared to contain 5 mg/mL hydralazinehydrochloride (prepared in Example 2), 0.325 mg/mL methyl paraben, 0.175mg/mL propyl paraben, and 100 mg/mL propylene glycol or poly(ethyleneglycol) in sterile water for injection. In addition, individualpreparations were prepared to contain poly(ethylene glycol) (PEG) havingan average molecular weight of 200, 400, 600, 1,000, 3,000, 5,000, or10,000 Daltons (identified as “PEG-xxxx”), each PEG meeting U.S.Pharmacopeial monograph standards for absence of ethylene oxide andethylene glycol. Each formulation was packaged in a glass bottlecontaining either no metal or a strip of stainless steel metal (“SS”)that was closed and sealed with an elasteomeric stopper.

Each formulation was observed for a period of 24 hours. Representativeobservations at 24 hours are presented in Table 4 unless a differenttime of observation is noted.

TABLE 4 Preparation of Stable Hydralazine Hydrochloride PharmaceuticalComposition. Formulation Solution Characteristics Post-Packaging (Timeof Observation) Containing No Metal SS304 SS316 SS316L Propylene GlycolClear, colorless Purple (<15 min.) Purple (<15 min.) Purple (<15 min.)PEG-200 Clear, colorless Clear, colorless Clear, colorless Clear,colorless PEG-400 Clear, colorless Clear, colorless Clear, colorlessClear, colorless PEG-600 Clear, colorless Clear, colorless Clear,colorless Clear, colorless PEG-1000 Clear, colorless Clear, colorlessClear, colorless Clear, colorless PEG-3000 Clear, colorless Clear,colorless Clear, colorless Clear, colorless PEG-5000 Clear, colorlessClear, colorless Clear, colorless Clear, colorless PEG-10000 Clear,colorless Clear, colorless Clear, colorless Clear, colorless PEG-20000Clear, colorless Clear, colorless Clear, colorless Clear, colorless“Clear” refers to solutions containing no visible particulate matter oryellow precipitates.

The present invention has been described in detail using specificexamples to illustrate the preferred embodiments of the invention.However, it will be obvious to those skilled in the art that variousmodifications thereto can be made without departing from the spirit andscope thereof.

1. A sterile aqueous injectable pharmaceutical composition suitable forparenteral administration comprising a therapeutically effective dose ofa hydralazine hydrochloride composition in a pharmaceutically acceptablecarrier or diluent, the aqueous injectable pharmaceutical compositionfurther comprising polyethylene glycol and sterile water for injection,wherein said hydralazine hydrochloride composition comprises hydralazinehydrochloride, less than about 1% by weight of phthalazine compounds,less than about 0.0005% hydrazine by weight, and less than about 15parts per million metal ions, and wherein said pharmaceuticalcomposition has no visible particulate matter 30 months aftermanufacture, said pharmaceutical composition has less than 6000 10micron particles per container 30 months after manufacture and saidpharmaceutical composition has less than 600 25 micron particles percontainer 30 months after manufacture.
 2. The composition of claim 1wherein said injectable pharmaceutical composition is in a sealedcontainer.
 3. The composition of claim 1 wherein the therapeuticallyeffective dose is from about 5 to about 20 mg and the concentration ofhydralazine hydrochloride is about 5 mg/ml.
 4. The composition of claim1 wherein the hydralazine hydrochloride concentration is from about 3.0to about 20 mg/ml.
 5. The composition of claim 1 wherein the hydralazinehydrochloride concentration is from about 3.0 to about 5.0 mg/ml.
 6. Thecomposition of claim 1 wherein the polyethylene glycol is essentiallyfree of ethylene oxide and ethylene glycol.
 7. A sterile aqueouspharmaceutical composition comprising a hydralazine hydrochloridecomposition comprising from about 3 to about 20 mg/ml hydralazinehydrochloride, the aqueous pharmaceutical composition further comprisingmethyl paraben, propyl paraben and polyethylene glycol in sterile waterfor injection, wherein the polyethylene glycol has an average molecularweight of 200, 400, 600, 1,000, 3,000, 5,000, or 10,000 Daltons and isessentially free of ethylene oxide and ethylene glycol, wherein saidhydralazine hydrochloride composition comprises the hydralazinehydrochloride, less than about 1% by weight of phthalazine compounds,less than about 0.0005% hydrazine by weight, and less than about 15parts per million metal ions.
 8. The composition of claim 7 wherein theconcentration of hydralazine hydrochloride is from about 3 to about 5mg/ml.
 9. The composition of claim 8 wherein the concentration ofhydralazine hydrochloride is about 5 mg/ml.
 10. A sterile aqueousinjectable pharmaceutical composition suitable for parenteraladministration in a sealed container comprising a hydralazinehydrochloride composition comprising from about 0.5 to about 40 mg/mlhydralazine hydrochloride in a pharmaceutically acceptable carrier ordiluent wherein said hydralazine hydrochloride composition compriseshydralazine hydrochloride, less than about 1% by weight of phthalazinecompounds, less than about 0.0005% hydrazine by weight, and less thanabout 15 parts per million metal ions, said injectable pharmaceuticalcomposition having no visible particulate matter after storage at 40° C.at 118 days after manufacture, less than 3,000 10 micron particles percontainer after storage at 40° C. at 118 days after manufacture, andless than 200 25 micron particles per container after storage at 40° C.at 118 days after manufacture.
 11. The composition of claim 10 whereinthe concentration of hydralazine hydrochloride is about 5 mg/ml.
 12. Thecomposition of claim 10 wherein said pharmaceutical composition has novisible particulate matter after storage at 40° C. at 118 days aftermanufacture, about 2370 or fewer 10 micron particles per container afterstorage at 40° C. at 118 days after manufacture, and about 160 or fewer25 micron particles per container after storage at 40° C. at 118 daysafter manufacture.
 13. The composition of claim 12 having about 5 mg/mlhydralazine hydrochloride after storage at 40° C. at 118 days aftermanufacture.
 14. A sterile aqueous pharmaceutical composition comprisingabout 5 mg/ml hydralazine hydrochloride, about 0.1625 mg/ml methylparaben, about 0.0875 mg/ml propyl paraben and 100 mg/ml polyethyleneglycol in sterile water for injection, wherein the polyethylene glycolhas an average molecular weight of 200, 400, 600, 1,000, 3,000, 5,000,or 10,000 Daltons and is essentially free of ethylene oxide and ethyleneglycol, wherein said aqueous pharmaceutical composition comprises lessthan about 1% by weight of phthalazine compounds, less than about0.0005% hydrazine by weight, and less than about 15 parts per millionmetal ions.
 15. The composition of claim 7, wherein the methyl parabenis at a concentration of about 0.1625 mg/ml and the propyl paraben is ata concentration of about 0.0875 mg/ml.
 16. The composition of claim 7,wherein the methyl paraben is at a concentration of about 0.325 mg/mland the propyl paraben is at a concentration of about 0.175 mg/ml. 17.The composition of claim 7, wherein the polyethylene glycol is at aconcentration of about 100 mg/ml.